Selective elimination of cancer cells is an important key issue in treating cancer. During malignant conversion and progression, various genetic changes occur in cells (Vogelstein, B. et al., Trends Genet 9, 138-41 (1993)). Such mutations could be targets of gene therapies for cancer.
Some types of genes exhibit a selective killing effect on cancer cells when overexpressed. Representative examples of such genes include p53 (Chen, P. L. et al., Science 250, 1576-80 (1990); Fujiwara, T. et al., J Natl Cancer Inst 86, 1458-62 (1994); and Nielsen, L. L. et al., Cancer Gene Ther 4, 129-38 (1997)) and mda-7 (Fisher, P. B. et al., Cancer Biol Ther 2, S23-37 (2003)), which have been known as antioncogenes.
Meanwhile, the REIC/Dkk-3 gene has been known as a gene involved in cell immortalization. It has been reported that expression of the gene is inhibited in cancer cells (see WO01/038523, Tsuji, T. et al., BiochemBiophys Res Commun 268, 20-4 (2000), Tsuji, T. et al., BiochemBiophys Res Commun 289, 257-63 (2001), Nozaki, I. et al., Int J Oncol 19, 117-21 (2001) and Kurose, K. et al., J Urol 171, 1314-8 (2004)).
The REIC/Dkk-3 gene is a member of the Dkk family and has been known to interfere with Wnt signal transduction via Wnt receptors (see Bafico, A. et al., Nat Cell Biol 3, 683-6 (2001) and Hoang, B. H. et al., Cancer Res 64, 2734-9 (2004)). The Wnt genes play pleiotropic roles in critical biological contexts, including cell growth, differentiation, malignant transformation, and the like (see Moon, R. T. et al., Science 296, 1644-6 (2002)). Therefore, similarly, Dkk family members (including 4 genes that have been known to exist in humans) are thought to fulfill important functions regarding cell growth, differentiation, and malignant transformation. However, most of their functions have not yet been elucidated.